Studies in the branch have been established to investigate the role of protooncogene alleles in cancer susceptibility, and the role of oncogenes in carcinogen-induced human tumors. To investigate the role of oncogenes in chemical carcinogenesis, fixed tissue blocks have been obtained from approximately 50 cases of benzidine or beta-naphthylamine associated bladder cancer, and 100 bladder cancer cases without such exposures. In addition, a small number of cyclophosphamide associated bladder tumors have been obtained. The polymerase chain reaction (PCR) is being used to amplify H- K- and N-ras genes followed by oligonucleotide probing or direct sequencing for oncogene activating mutations at codons 12, 13, and 61. The pattern and mutational spectra of oncogene activation will be compared between benzidine/beta-naphthylamine associated tumors, cyclophosphamide associated tumors and those which arose spontaneously or were smoking-associated. In a similar study, fixed tissue samples of lung tumors have been obtained from individuals with primary lung cancers who had high dose occupational exposure to one of a variety of known lung carcinogens, including radon, asbestos, nickel, chromate, and vinyl chloride. PCR with oligonucleotide probing or direct sequencing is being used to characterize K-ras family mutations which will then be correlated with exposure information. A case control study of bladder cancer has been initiated to investigate whether restriction fragment length polymorphisms of proto-oncogenes correlate with cancer susceptibility. Exposure information, along with blood, urine, and tumor tissue, are being collected on 200 bladder cancer cases and 200 controls. Southern blots are being used to determine whether rare alleles of H-ras and other proto-oncogenes correlate with cancer susceptibility. The interaction between genotype and exposure will also be explored.